Preliminary Results from a Phase 2 Study to Evaluate ACE-083, a Local Muscle Therapeutic,

in Patients with Facioscapulohumeral Muscular Dystrophy

Florian P Thomas1, Michael Shy2, David Herrmann3, Jeffrey Statland4, David Walk5, Colin Quinn6,Nicholas Johnson7, SH Subramony8, Chafic Karam9, Tahseen Mozaffar10, Chad E Glasser11, Barry Miller11,

Ashley Leneus11, Robert K Zeldin11, Kenneth M Attie11

1Hackensack UMC and Hackensack Meridian School of Medicine, 2University of Iowa, 3University of RochesterMedical Center, 4University of Kansas Medical Center, 5Dept. of Neurology, University of Minnesota,

6University of Pennsylvania, 7University of Utah, 8University of Florida, 9Oregon Health & Science University, 10University ofCalifornia Irvine, 11Acceleron Pharma

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Disclosures

• Acceleron Pharma supported this study

• Other disclosures• Sanofi, Pharnext, Novartis, Genentech

• Editor-in-chief of Journal of Spinal Cord Medicine

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Charcot-Marie-Tooth (CMT) Disease – Introduction

▪ CMT is the most common inherited peripheral neuropathy, with an incidence of 1 in 25001

▪ CMT is a slowly progressive neuropathy that causes predominantly distal arm and leg weakness, motor and sensory nerve loss, and foot and ankle deformities

• Tibialis anterior (TA) weakness is a cardinal manifestation of disease, with virtually all patients developing weak ankle dorsiflexion, often early in their disease course

• Weakness of the TA muscle causes foot drop, impairs ambulation, and increases the risk of falls

▪ CMT has substantial unmet medical need with no drug therapies currently available

• Orthotics and bracing can be helpful, but compromise gait mechanics and may lead to muscle atrophy and discomfort

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1Saporta MA, et al. Neurol Clin 2013; 31: 597-6192Charcot-Marie-Tooth Disease (CMT), https://www.mda.org/disease/ charcot-marie-tooth [Accessed 29 April 2019]

CMT Pathophysiology2

Damage to peripheral nerves results in distal sensory disruption and muscle atrophy

• >80 genes identified

• Several sub-types (CMT 1, 2, 4 and X)

• Initially affects myelin sheath (eg, Type 1) or nerve axon (eg, Type 2)

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ACE-083 – A Locally-Acting Muscle Therapeutic

ACE-083 is a locally-acting protein therapeutic in the TGF-β superfamily consisting of a modified form of human follistatin that binds GDF8 (myostatin) plus other negative regulators of skeletal muscle

Designed to be locally injected in affected muscles to increase muscle mass and strength

Increased muscle mass demonstrated in healthy volunteers1 and patients with FSH muscular dystrophy2

Tibialis anterior and biceps were selected as initial muscle targets for a locally acting therapeutic

1 Glasser CE, et al. Muscle Nerve. 2018; 57:921-9262 Statland J, et al. World Muscle Society 2018 Poster 365

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ACE-083 CMT Study Design

Key Eligibility Criteria: Age ≥ 18 years Genetically-confirmed CMT1 or CMTX, or, genetically-

confirmed first-degree relative and clinical signs/symptoms of CMT1 or CMTX

Left and right ankle dorsiflexion weakness 6-minute walk distance ≥ 150 meters

Treatment: ACE-083 injection into tibialis anterior (TA) muscle bilaterally

every 3 weeks

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Part 1 – 3 mos open-label ACE-083

Cohort 3ACE-083 240 mg

N=6

Cohort 1ACE-083 150 mg

N=6

Cohort 2ACE-083 200 mg

N=6

Part 2 – 6 mos placebo-controlled 6 mos open-label

ACE-083 240 mgN=20

PlaceboN=20

ACE-083 240 mgN = 20

ACE-083 240 mgN =20

6 months6 months

Ra

nd

om

ize

1:1

Assessments and Selected Outcome Measures: Safety and tolerability Total and contractile muscle volume (TMV, CMV),

fat fraction (FF) by 2-pt Dixon MRI Strength by hand-held dynamometry and manual

muscle testing 6-minute walk test, 10m walk/run CMT-Health Index

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Baseline Characteristics

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ACE-083 CMT Study – Baseline Characteristics, Part 1

6MWD = 6-minute-walk distanceMedian (range), unless otherwise indicated

Preliminary data as of 18 March 20197

Cohort 1150 mg

N=6

Cohort 2200 mg

N=6

Cohort 3240 mg

N=6

Overall N=18

Age, yr 35 (23-62) 39 (18-61) 52 (31-58) 48 (18-62)

Gender, n (%)MaleFemale

3 (50%)3 (50%)

3 (50%)3 (50%)

2 (33%)4 (67%)

8 (44%)10 (56%)

Duration of symptoms, yr 31 (14-61) 30 (6-51) 12 (2-25) 23 (2-61)

CMT subtype, n (%)CMT1ACMT1BCMTX1

4 (67%)1 (17%)1 (17%)

5 (83%)0

1 (17%)

2 (33%)3 (50%)1 (17%)

11 (61%)4 (67%)3 (17%)

Total muscle mass, g 66 (38-87) 70 (40-85) 92 (73-141) 78 (38-141)

Fat fraction, % 29 (10-45) 31 (15-37) 27 (9-44) 30 (9-45)

6MWD, m 418 (236-588) 381 (324-501) 459 (265-620) 411 (236-620)

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ACE-083 CMT Study – Baseline Correlations, Part 1 Patients

Baseline 6MWD correlated with 10mW/R and the CMT-HI Mobility Subscore

8 Preliminary data as of 18 March 2019

6MWD = 6-minute walk test distance; 10mW/R = 10-meter walk/run; CMT-HI = CMT Health-Index

10mW/R Time (s) CMT-HI Mobility Subscore

6M

WD

(m

)

6M

WD

(m

)

r = -0.77p < 0.001n = 18

r = -0.74p < 0.001n = 18

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Part 1 Dose Escalation Results

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ACE-083 CMT Study – Related Adverse Events, Part 1

Preliminary data as of 18 March 2019

Possibly or Probably Related Adverse Events Occurring in ≥10% Patients Overall

▪ ACE-083 was generally well tolerated in subjects treated for up to 3 months (5 doses)

• Most common adverse events were injection site reactions, muscle spasms, and myalgia

• Most adverse events were mild or moderate (grades 1-2)

▪ No clinically significant laboratory abnormalities on treatment

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Preferred Term, n(%)(Cohort 1

150 mg (N=6)Cohort 2

200 mg (N=6)Cohort 3

240 mg (N=6)OverallN=18

Injection site discomfort 3 (50%) 2 (33%) 3 (50%) 8 (44%)

Injection site bruising 1 (17%) 2 (33%) 2 (33%) 5 (28%)

Injection site erythema 2 (33%) 1 (17%) 1 (17%) 4 (22%)

Muscle spasms 1 (17%) 2 (33%) 1 (17%) 4 (22%)

Myalgia 2 (33%) 0 2 (33%) 4 (22%)

Injection site pain 1 (17%) 1 (17%) 1 (17%) 3 (17%)

Injection site swelling 1 (17%) 1 (17%) 1 (17%) 3 (17%)

Pain in extremity 1 (17%) 1 (17%) 1 (17%) 3 (17%)

Injection site pruritus 1 (17%) 0 1 (17%) 2 (11%)

Joint stiffness 1 (17%) 0 1 (17%) 2 (11%)

Muscle tightness 1 (17%) 0 1 (17%) 2 (11%)

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ACE-083 CMT Study – Total Muscle Volume, Part 1Percent Change from Baseline to Day 106 (3 weeks post last dose)

Preliminary data as of 18 March 201911

(Average of right and left sides)

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ACE-083 CMT Study – Intramuscular Fat Fraction (Percent), Part 1Absolute Change from Baseline to Day 106 (3 weeks post last dose)

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(Average of right and left sides)

Preliminary data as of 18 March 2019

Intramuscular fat fraction was measured by 2-pt Dixon MRI scan of the entire tibialis anterior muscle

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ACE-083 CMT Study – Contractile Muscle Volume, Part 1Percent Change from Baseline to Day 106 (3 weeks post last dose)

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(Average of right and left sides)

Contractile Muscle Volume = Total Muscle Volume * [(100 – Fat Fraction)] / 100

Preliminary data as of 18 March 2019

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ACE-083 CMT Study – Conclusions, Part 1

ACE-083, a locally-acting muscle therapeutic, acting on myostatin plus other inhibitors of muscle growth, had a favorable safety profile and was generally well-tolerated over a 3-month treatment period in patients with CMT injected in the tibialis anterior (TA)

Baseline 6MWD correlated with 10m Walk/Run and CMT-HI Mobility Subscore

Changes observed in pharmacodynamic outcome measures at 3 weeks post last dose:

o Mean % increases of >12% total muscle volume and >15% contractile muscle volume

o Mean absolute decrease in fat fraction of >3% in the 200 mg and 240 mg group

These results support continued investigation of ACE-083 in neuromuscular diseases

o Placebo-controlled Part 2 of this Phase 2 CMT study is now enrolling (NCT03124459)

o Placebo-controlled Part 2 of a separate Phase 2 in FSHD study is ongoing (NCT02927080)

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Acknowledgements

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The authors wish to thank the patients and their families for their participation and contributions as well as the following team members:

Sub-Investigators: Amy Visser, Mazen Dimackie, Georgious Manousakis, Peter Creigh, Russell Butterfield, Lauren Elman, Eric Mittelmann, Nivedita Jerath, Ali Habib, Ludwig Gutmann, Gene Han, Clement Yang

Clinical Evaluators: Katy Eichinger, Deanna DiBella, Melissa McIntyre, Amelia Wilson, Lindsay Baker, Keegan Kitzgerald, Jeff Schilmgen, Denise Davis, Patrick Tierney, Kyle Cunningham, Lauren Draper, Chelsea Bacon, Melissa Currence, Laura Herbelin, Ludo De Wolf, Hope Anneliese Lane, Samantha Pierre, Raphael Kupferman, Molly Stark, Sandy Swanson

Clinical Site Coordinators: Bryant Gordon, Jeanette Overton, Sonya Aziz-Zaman, Amanda Cowsert, Nicole Kressin, Ayla McCalley, Natalya Burlakova, Christine Cavallo, Janet Sowden, Diana Dimitrova

MedPace: Richard Scheyer, Georgiana Salyers, Megan Kolthoff, Taylor Meece, Stephanie Porter, Gina Kavanaugh, Emily Birkmeyer, Katie Ard, Jacob Giltrow, Elizabeth Do, Sabrina Lesh, Courtney Pearce, Leslie Foertsch

Acceleron: M Yuen, B Leibo, J Sun, S Qamar, S Harrison, C Barron, M Fowler, J Reynolds, T Nguyen, S Celikovic

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